Neuronal ABCA7 loss of function and Alzheimer’s disease

项目摘要/摘要 杰克逊维尔梅奥诊所 目前的遗传学研究表明，晚发性阿尔茨海默病(AD)的易感基因座是相关的 与脂类代谢有关。而ATP结合盒转运体A7(ABCA7)基因变异强烈 与AD风险相关的是，ABCA7的提前终止密码子(PTC)突变显著增加 早发性和晚发性AD的风险。ABCA7属于ABC转运蛋白家族 脂类和其他脂类相关分子在细胞膜上的分布。因此，探索 脂质代谢中的ABCA7应为我们确定中枢致病途径提供重要线索 广告。虽然ABCA7在脑细胞类型中的神经元表达最高，但我们的初步研究表明 ABCA7缺乏症改变线粒体相关脂质的组成，损害线粒体功能 伴随着人类诱导性皮质类器和神经元的突触调节障碍 多能干细胞(IPSCs)。此外，RNA测序分析还发现，与脂肪相关的通路 ABCA7主要影响线粒体酸性β氧化和细胞膜动态平衡 小鼠大脑的缺陷。由于血脂对神经功能的调节有重要作用，我们 假设ABCA7功能丧失改变了细胞器间的脂代谢，并干扰了 线粒体在神经元中的功能，导致衰老和突触功能障碍 广告。因此，这项建议的独特目的是剖析ABCA7缺乏对血脂代谢的影响。 神经元，参与AD相关表型，包括线粒体失调和突触 功能障碍。在目标1中，我们将研究ABCA7缺乏如何影响脂代谢，线粒体 功能，以及使用IPSC来源的神经元和皮质器官的AD相关表型。在目标2中，我们将 利用神经元特异性ABCA7基因敲除小鼠剖析神经元ABCA7在AD相关表型中的作用 有或没有淀粉样变的模型，并伴有单细胞-RNA测序。在《目标3》中，我们将 探讨ABCA7缺乏对突触的影响，包括线粒体功能和血脂谱，通过 分离常规ABCA7基因敲除小鼠的突触体以及神经元特异性ABCA7基因敲除 患有或不患有淀粉样变的小鼠。总的来说，这些研究应该为我们提供新的见解 ABCA7牙线干扰阿尔茨海默病发病的分子机制 神经元脂质动态平衡。

PROJECT SUMMARY/ABSTRACT MAYO CLINIC JACKSONVILLE Current genetic studies indicate that susceptibility loci in late-onset Alzheimer’s disease (AD) are correlated with lipid metabolism. While ATP-binding cassette transporter A7 (ABCA7) gene variants are strongly associated with AD risk, the premature termination codon (PTC) mutations in ABCA7 significantly increases the risk for both early-onset and late-onset AD. ABCA7 belongs to the ABC transporter family regulating distribution of lipids and other lipid-related molecules across cellular membranes. Thus, exploring functions of ABCA7 in lipid metabolism should provide us important clues to determine the central pathogenic pathway for AD. While ABCA7 expression is the highest in neurons among brain cell types, our preliminary study showed that ABCA7 deficiency alters the compositions of mitochondria-related lipids and impairs mitochondria function accompanied with synaptic dysregulation in the cortical organoids and neurons derived from human induced pluripotent stem cells (iPSCs). In addition, RNA-sequencing analysis also found that pathways related to fatty acid β-oxidation in mitochondria and cellular membrane homeostasis are predominantly affected by ABCA7 deficiency in mouse brains. As lipids substantially contribute to the regulation of neuronal functions, we hypothesize that ABCA7 loss of function alters the lipid metabolism among cellular organelles, and disturbs mitochondria functions in neurons, resulting in neurodegeneration and synaptic dysfunction during aging and AD. Therefore, this proposal uniquely aims to dissect how ABCA7 deficiency impacts lipid metabolism in neurons and contributes to AD-related phenotypes including mitochondria dysregulation and synaptic dysfunction. In Aim 1, we will examine how ABCA7 deficiency influences lipid metabolism, mitochondria function, and AD-related phenotypes using iPSC-derived neurons and cortical organoids. In Aim 2, we will dissect roles of neuronal ABCA7 in AD-related phenotypes using neuron specific Abca7 knockout mouse models with or without amyloid pathology, accompanied with single cell-RNA sequencing. In Aim 3, we will explore impacts of ABCA7 deficiency on synapses, including mitochondria functions and lipid profiles, by isolating synaptosomes from conventional Abca7 knockout mice as well as neuron specific Abca7 knockout mice with or without amyloid pathology. Collectively, these studies should provide us new insights for the molecular mechanisms in which ABCA7 floss of function causes the pathogenic processes of AD by disturbing neuronal lipid homeostasis.